Synthesis of some acetylenic acids

Chemistryand Physicsof Lipids 13 (1974)239-248 O North-HollandPublishing Company

S Y N T H E S I S O F SOME A C E T Y L E N I C ACIDS N.W. GILMAN and B.C. HOLLAND

ChemicalResearchDepartment,Hoffmann-LaRocheInc., Nutley, New Jersey07110, USA Received May 6, 1974, accepted July 26, 1974

All of the mono-ynoic acids (excludingboth terminal and conjugated acetylenic acids) of chain length C10 to C14 have been prepared. None of these acids show any useful inhibition of the enzyme PG-Synthetasewhich is used in the synthesis of prostaglandins from arachidonic acid.

I. Introduction The enzymatic conversion of arachidonic acid (all cis-5,8,11,14-eicosatetraenoic acid) to PGE 2 with the prostaglandin synthetase enzyme is a known process [1 ]. A study on the inhibition of this conversion with polyacetylenic acids such as 5, 8, 11,14-eicosatetraynoic acid and 9,12-octadecadiynoic acid has been reported [2,3]. As part of a program concerned with the synthesis of PG-Synthetas inhibitors, all of the mono-ynoic acids of chain length ClO to C14 have been prepared with the exception of both terminal and conjugated acetylenic acids. None of these compoimds have exhibited any useful inhibition of the PG-Synthetase enzyme (test resuits were obtained by Dr. J. Paulsrud of our Biochemical Nutrition Department and will be reported in in a separate publication).

II. Synthesis With the exceptions noted in the discussion, the A4 and A 5 alkynoic acids were prepared utilizing the alkylation of an ~o-acetylenic acid with an alkyl halide; the A6--A12 acids were synthesized by the alkylation of an 1-alkyne with an o~-bromo acid (see eq. (1) and (2)) CH3(CH2)xX + HC-~C(CH2)yCO2H ~ CH3(CH2)xC-=C(CH2)yCO2H A4--A 5 acids

(1)

CH3(CH2)x C=-CH+Br(CH2)y CO2H'~'CH3(CH2)x CW:C(CH2)y CO2H A6--A12 acids

(2)

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N. hr. Gilman, B.C. Holland, Synthesis of some acetylenic acids

The A3 acids were prepared by the alkylation of the dilithio anion of 3-butyn-1ol, 1, with bromalkanes followed by oxidation as shown in equation (3). HC~CCH2CH2OH

(1) LiNH2 (2) CH3(CH2)xBr> CH3(CH2)xC~=CCH2CH20H

1

2

Cr03, CH3(CH2) x C-=CCH2CO2H

(3)

3 A. The A 3 acids

With the exception of 3-decyn-l-ol [4], the alcohols 2 (n = 6-9) are new compounds and were prepared in yields of 59-68% by the method of Ames et al. [5]. The oxidation of the alcohols to the carboxylic acids with chromium trioxide gave substantial amounts of ester by-products, 4 as shown below CrO3 CH3(CH2)xC~CH2CH2OH

>

2 CH3(CH2)xC~CCH2CO2H+CH3(CH2)xC=CCH2CO(CH2) 2

x = 5-9

/

C Ill C

I

fCH2)x I CH3

(4)

Consequently, a method was developed which allows the oxidation of alkynols to the corresponding acids to be carded out in high yields with only minimum amounts of esters 4 being formed. The procedure used involves the slow rate of addition of a dilute solution of the alcohol in acetone to chromium trioxide in H2SO 4 . Additional details on this process will be published elsewhere (B.C. Holland and N.W. Gilman, Synthetic Communications, in press). B. The A 4 acids

The A4 acids 6 were prepared by the alkylation of the dilithio anion of 4-pentynoic acid 5 with alkyl bromides in hexamethylphosphoramide (HMPA), eq. (5). The only member of this series which has been previously reported is 4-decynoic acid [6]

iV. I¢. Gilman, B.C. Holland, Synthesis of some acetylenic acids

HC~C(CH2)2CO2H (1) n-BuLl, HMPA., CH3(CH2)xC_=C(CH2)2CO2 H 5 (2)CH 3 (cn2)xBr 6

241

x=4-8 (5)

From an examination of the literature, it appears that there has been only one other synthesis of an acetylenic acid by the direct alkylation of an w-acetylenic acid with an alkyl halide. The condensation of 10-undecynoic acid and 1-bromoheptane in the presence of LiNH 2 in THF led to 10-octadecynoic acid [7]. It has now been found that this type of alkylation can be easily carried out in good yield by using FIMPA as a solvent. A similar use of HMPA as a solvent for the alkylation of simple acetylenes has recently been published [8]. C TheA5acids

The A5 acids 8 were prepared by the alkylation of alkyl bromides with the dilithio anion of 5-hexynoic acid 7, eq. (6). Again, the use of HMPA as a solvent for the reaction made these compounds readily available. In this series, only 5-tridecynoic acid is new. 5-Decynoic [9], 5-undecynoic [10], 5-dodecynoic [4] and 5-tetradecynoic [11 ] acids had been prepared by alternate methods. HC.~C(CH2)3CO2 H (1) n-BuLi,HMPA ~ CH3(CH2)xC_C(CH2)3CO2 H (2) C H3(CIOxBr 7 8

x=3-7 (6)

D. The A 6 acids

The A 6 acids 9 were synthesized by treatment of a litliio-alkyne with 5-bromopentanoic acid (prepared by hydrolysis of 5-bromovaleronitrile with 48% HBr), utilizing HMPA as a solvent. Alkylations of this type using tetrahydrofuran (THF) as a solvent have been reported [ 12]. CH3(CH2)xC~C H (1) n-BuLi,HMPA ~ CH3(CH2)xC~C(CH2)4CO2H (2) Br (CH2)4CO2H 9

x=2_ 6 (7)

Only 6-tetradecynoic acid is a new compound; 6-decynoic [ 19], 6-undecynoic [13], 6-dodecynoic [10] and 6-tridecynoic [14] acids have been prepared previously by alternate methods. E. The A 7 acids

With the exception of 7-decynoic acid, the A 7 acids 10 were prepared from 6-bro. mohexanoic acid (obtained from Aldrich Chemical Co.) and 1-1ithio alkynes in HMPA.

242

N. I¢. Gilman, B.C. Holland, Synthesis o f some acetylenic acids

CH3(CH2)xC=CH (1) n-BuLi,HMPA > CH3(CH2)xCZ_C(CH2)sCO2 H (2) Br(CH2)5 CO2H 1o

x=2-5

(8)

7-Decynoic acid 11 was obtained by the alkylation of 7-octynoic acid [ 15] with ethyl bromide. HC_=C(CH2)5CO2H (1) (2)nBuLi,HMPA CH3CH2Br > CH3CH2C-=C(CH2)5CO2H 11

(9)

7-Decynoic and 7-undecynoic acids are new compounds; 7-do-decynoic [14], 7tridecynoic [14], and 7-tetradecynoic [14] acids have been prepared previously. F. The A 8 acids

The treatment of a 1-1ithio alkyne with 7-bromoheptanoic acid [ 16] in HMPA gave the A 8 acids 12 as shown in eq. (10). 8-Tridecynoic acid 14 was prepared by a longer route which involved the alkylation of 1-hexyne with 1-chloro-6-iodohexane in HMPA to give 13, followed by treatment of 13 with sodium cyanide and subsequent basic hydrolysis of the unisolated nitrile as shown in eq. (11): CH3(CH2)xC=C H (1) n-BuLi,HMPA ~ CH3(CH2)xC=C(CH2)6CO2H (2) Br(CH2)6CO2H 12 x=0,1,2,4 CH3(CH2) 3 C =CH

(10)

(1) CH3Li;HMPA , CH3(CH2) 3 C-C(CH2)6CI (2) C1(CH2)61 13

(1) NaCN > CH3(CH2) (2) NaOH 3

)

6CO2 H C l(CH2• C

(ll)

In this series, only 8-dodecynoic [ 17] and 8-tetradecynoic [ 18] acids have been previously reported. G. The A 9 acids

The alkylation of lithio-alkynes with 8-bromo-octanoic acid [ 19] in HMPA gave the first three members of this series 15 (x = 0 - 2), as shown in eq. [ 12]. The last member, 9-tetradecynoic acid 16, was prepared by condensing diethylmalonate with 1-chloro-7-dodecyne 13 followed by basic hydrolysis and decarbonylation of the unisolated intermediate diaeid.

243

N. I¢. Gilman, B. C Holland, Synthefis of some acetylenic acids

CH ( C H ) Cm CH (1) nBuLi,HMPA > CH3(CH2)xC-C(CH2)7CO2H 3 2x (2) Br (CH2)7CO2H 15

x=0-2 (12)

(1) NaCH(CO2E02 CH3(CH2)3C -C(CH2)6C1 (2) NaOH > CH3(CH2)3C -C(CH2)7CO2H 13

16

(13)

All of the A 9 acids: 9-undecynoic [20], 9-dodecynoic [17], 9-tridecynoic [21] and 9-tetradecynoic [12] acid have been previously synthesized by other methods. H.. The A 10 acids

The alkylation of 9-bromononanoic acid [22] with 1-1ithio alkynes in HMPA gave the A10 acids 17, as shown in eq. (14). CH3(CH2) x C - C H (1) n-BuLi,HMPA -, CH3(CH2)xC=C(CH2)8CO2H (2) Br(CH2)8CO2 H 17

x=0_ 2 (14)

Only 10-dodecynoic acid [17] has been reported in the literature. I. The A 11 acids

The new A 11 acids 18 were obtained by the alkylation of 10-bromodecanoic acid [23] with 1-1ithiopropyne and 1-1ithiobutyne respectively, see eq. (15). CH3(CH2) x C=CH (1) n-BuLi,HMPA (2) Br (CH2)gCO2H ' CH3(CH2)x C -=C(CH2)9CO2H 18

x=0-1

(15)

£ The A 12 acid

The only possible A 12 acid, 12-tetradecynoic acid 19, was synthesized from 11bromoundecynoic acid (obtained from Aldrich Chemical Co.) and 1-1ithio propyne, as shown in eq. [16]. CH3C -=CH (1) n-BuLl,HMPA (2) Br (CH2)10CO2H ' CH3 C =C(CH2)10CO2H 19

(16)

HI. Experimental All melting points are corrected. Infrared (IR) spectra were determined on either a PE. 137 or a Beckman IR-9 instrument. Nuclear magnetic resonance spectra were

244

iV. 1tl. Gilman, B.C. Holland, Synthesis o f some acetylenic acids

Table 1 Physical properties and analytical data for all new intermediates. Compound

3-Undecyn-l-ol 3-Dodecyn-l-ol 3-Tridecyn-l-ol 3-Tetradecyn-l-ol 1-Chloro-7-dodecyne

Yield m.p./b.p.°C

65 59 63 68 44

Empirical formula

Calculated C H

C

CllH20 O C12H220 C13H240 C14H260 C12H21C1

78.51 1 1 . 9 8 79.06 12.16 79.53 12.32 79.94 12.46 71.80 10.54

78.34 79.16 79.69 79.67 71.96

Empirical formula

Calculated C H

C

C10H160 2 CllH180 2 C12H2002 C13H220 2 C14H240 2 C10H1602 CllH1802 C12H200 2 C13H220 2 C14H240 2 C10HI602 CllH1802 C12H2002 C13H220 2 C14H240 2 C10H1602 CllH180 2 C12H2002 C13H220 2 C14H240 2 C10H160 2 CllH1802 C12H2002 C13H2202 C14H240 2 C10H160 2 CllH180 2 C12H200 2 C13H2202 C14H240 2 C11H1802 C12H2002

'1.40 9.59 12.49 9.96 73.43 10.27 74.24 10.54 74.95 10.~8 71.40 9.59 72.49 9.96 73.43 10.27 74.24 10.54 74.95 10.78 71.40 9.59 72.49 9.96 73.43 10.27 74.24 10.59 74.95 10.78 71.40 9.59 72.49 9.96 73.43 10.27 74.24 10.59 74.95 1 0 . 7 8 71.40 9.59 72.49 9 . 9 5 73.43 10.27 74.24 10.54 74.95 10.78 71.40 9.59 72.49 9 . 9 6 73.43 10.27 74.24 10.54 74.95 10.78 72.49 9 . 9 5 73.43 1 0 . 2 7

71.37 9.72 7 2 . 5 3 9.91 73.56 10.51 73.99 10.77 74.79 11.00 71.36 9.80 72.52 10.18 73.24 10.60 74.50 10.80 74.68 10.90 7 1 . 5 1 9.84 72.59 10.17 73.40 10.50 74.02 10.71 74.89 10.97 71.34 9.56 72.73 9.75 73.35 10.08 74.19 10.47 74.87 10.76 71.12 9.85 72.14 9.93 73.69 10.26 74.23 10.61 74.76 10.74 71.29 9.72 72.19 9.82 73.19 10.18 74.11 10.35 74.76 10.74 72.29 10.16 7 3 . 1 5 9.99

79-80/0.25 mm 106-107/0.25 99-10110.50 115-116/0.35 75-78/0.35

Found H 12.05 11.97 12.29 12.72 10.39

Table 2 Physical properties and analytical data for all acids. Compound

3-Deeynoic acid 3-Undecynoicacid 3-Dodeeynoic acid 3-Tridecynoieacid 3-Tetradecynoicacid 4-Deeynoic acid 4-Undecynoic acid 4-Dodecynoicacid 4-Tridecynoic acid 4-Tetradecynoicacid 5-Decynoic acid 5-Undecynoicacid 5-Dodeeynoicacid 5-Tridecynoicacid 5-Tet~adecynoicacid 6-Deeynoie acid 6-Undecynoic acid 6-Dodecynoicacid 6-Tridecynoicacid 6-Tetradeeynoicacid 7-Decynoic acid 7-Undecynoicacid 7-Dodecynoicacid 7-Tridecynoicacid 7-Tetradeeynoicaeid 8-Decynoie acid 8-Undecynoicacid 8-Dodecynoicacid 8-Trideeynoic acid 8-Tctradecynoicacid 9-Undecynoic acid 9-Dodeeynoic acid

Yield m.p./b.p.° C

10a 32a 40 43 46 39a 37 35 34 32 20a 54 a 63a 21 51 a 43 a 36a 25a 45a 19 57 55 23a 43a 40a 39 49 39a 53b 25a 52a 60a

34- 36 4 1 - 42.5 4 7 - 49 54.5-56.5 58- 60 36.5-38 38.5-40.5 4 8 - 50 53- 55 59- 60 113-116/0.5 mm 112-115/0.4 122-123/0.3 125-135/0.35 34- 36 130-135/0.4 mm 125-135[0.15 125/0.2 135-145/0.2 139-144/0.3 98-100/0.1 mm 127-135/0.15 130-133/0.05 115/0.15 135-139/0.45 41.5-42.5 120-123/0.25 41.5-42.5 130-134/1.2 150-153/0.15 58.5-59.5 39.5-41

Found H

N. W.Gilman, B. C Holland, Synthesis of some acetylenic acids

245

Table 2 (continued) Compound 9-Tfidecynoicaeid 9-Tetradecynoic acid 10-Dodecynoicacid 10-Tfidecynoic add 10-Tetradecynoicacid ll-Tridecynoicaeid ll-Tetradeeynoicaeid 12-Tetradecynoieaeid

Yield m.p./b.p.° C 43 a 30a,b 77a 59 60 81 82 18

29-31 30-32 51-53 34-36 135/0.2 61-63 47-49 55-57

E m p i r i c a l Calculated formula C H

C

C13H2202 C14H2402 C12H2002 C13H2202 C14H2402 C13H2202 C14H2402 C14H240 2

74.49 10.36 74.96 10.89 73.35 10.21 74.23 10.24 74.98 11.06 73.01 10.39 73.77 10.68 74.81 10.96

74.24 10.54 74.95 10.78 73.43 10.27 74.24 10.54 74.95 10.78 74.24 10.54 74.95 10.78 74.95 10.78

Found H

a All of these compounds have been reported in the literature and the appropriate references are given in the discussion section. b The yield is based on 1-etfloro-7-dodeeyne. determined on a Varian T-60, A-60, or HA-100 spectrometer, using tetramethylsilane as an internal standard. Hexamethylphosphoramide was distilled from calcium hydride and stored over Linde 4A molecular sieves, n-Butyllithium was a 1.6 M solution in hexane obtained from Foote Mineral Co. All reactions involving lithium acetylides were carried out under an atmosphere of argon. The physical and analytical data for all new intermediates are given in table 1. The physical and analytical data for all acids synthesized are given in table 2. Spectral data for all compounds were consistent with the assigned structures. Only representative experimental details are given.

A. 3-Undecynoic acid, 3 (x = 6) To a cooled solution of 10 g (100 mmol) of chromium trioxide in 100 ml of 10 N H2SO 4 , was added over 7 hr, a solution Of 8.4 g (50 mmol) of 3-undecyn-l-ol in 500 ml of acetone. The internal temperature was maintained at 3-5°C. After concentration of the solution under reduced pressure, the residue was dissolved in H20 and extracted well with ether. The ether extracts were combined and extracted with two 150 ml portions of 3 N NaOH. The basic extracts were cooled in an icebath, acidified with 3 N HC1 and extracted with ether. The ether was removed on a rotary evaporator and the residue recrystaUized from petroleum ether (b.p. 30-60°C) to give 6.7 g (73%) of 3-undecynoic acid.

B. 4-Decynoic acid, 6 (x = 4) To a 3.43 g (35 mmol) of 4-pentynoic acid in 75 ml of HMPA (at 0°C under argon) was added 58 ml (70 mmol) of 1.2 M methyllithium in ether (n-butyllithium in hexane can also be used with similar results). The ice-bath was removed and after the temperattlre of the solution reached room temperature, 4.33 ml (5.28 g, 35 mmol) of 1-bromopentane was added. The mixture was stirred at room temperature

246

iV. I¢. Gilman, B.C. Holland, Synthesis o f some acetylenic acids

for 6 hr during which time the deep red color gradually faded to light yellow. After pouring into ice-water and acidifying with 3 N H2SO 4, the solution was extracted with ether. The ether extracts were washed with dilute brine in order to remove HMPA, dried (MgSO4) , concentrated and distilled to give a yellow oil, b.p. 110-117 °C/0.5 mm. The oil solidified on cooling and the resulting solid was recrystallized from pentane at - 7 8 °C to give 2.3 g (39%) of 4-decynoic acid as colorless plates, m.p. 36.5-38.0

°C.

C 6-Dodecynoic acid, 9 (x = 4) A solution of 1.6 M n-butyllithium in hexane (260 ml, 0.415 tool) was added dropwise to 54.0 ml (39.t g, 0.41 rnol) of 1-heptyne in 600 ml of HMPA cooled at 0 °C. Following the addition, 34.4 g (0.19 mol) of 5-bromopentanoic acid was added and the mixture stirred for 3 hr in an ice-bath. After pouring the solution into ice-water, 3N HC1 was added until the solution was acidic. After extraction with ether, the ether extracts were combined, washed with dilute brine, dried, concentrated and distilled to give 9.0 g (25%) of 6-dodecynoic acid as a pale yellow oil, b.p. 125 °C/ 0.2 mm.

D. 1-Chloro-7-dodecyne, 13 To a solution of 12.6 ml (9.03 g, 110 mmol) of 1-hexyne in 125 ml of HMPA, cooled in an ice-bath and under argon, was added, via syringe, 73 rnl (110 mmol) of 1.6 M methyllithium in ether. The solution was stirred for 20 min, then 12.3 g (50 mol) of 1-chloro-6-iodohexane was added via syringe. The temperature rose to 30 °C. After the addition of 30 ml of HMPA, the solution was cooled to 10 °C and an additional 12.3 g (50 mol) of 1-chloro-6-iodohexane was added. After stirring for 35 min in an ice-bath, the reaction mixture was poured into ice-water, acidified and extracted with ether. The ether extracts were washed with dilute brine, dried (Na2SO4), concentrated and distilled to give 8.86 g (44%) of 1-chloro7-dodecyne as a colorless liquid, b.p. 75-78 °C/0.35 ram.

E. 8-Tridecynoic acid, 14 A inixture of 2.6 g (53 mmol) of NaCN and 200 mg of NaI in 100 ml of dimethyl sulfoxide was heated to 80 °C. 1-Chloro-7-dodecyne 8.85 g (44 mmol), was added and the resulting mixture heated at 80 °C for 1.5 hr. After the addition of 500 mg of NaCN, heating was continued for 2 hr. The mixture was cooled, poured into ice-water and extracted with ether. The ether extracts were washed with dilute brine, dried (Na2SO4) and concentrated to give the crude cyano compound. Without purification, the crude product was refluxed for 46 hr with a mixture of 35 ml of ethanol and 250 ml of 3 N NaOH. After cooling, the solution was poured over

N. IV. Gilman, B.C Holland, Synthesis of some acetylenic acids

247

ice, acidified with 6 N H2SO4 and extracted with ether. The crude product was distilled to give 4.87 g (53%) of 8-tridecynoic acid as a colorless oil, b.p. 130-134 °C/1.2 ram.

F. 8-Decynoic acid, 12 (x = O) To a solution of 25 ml (excess) of propyne in 100 ml of ether, cooled at - 7 8 °C and under argon, was added 25 ml of HMPA followed by 96 ml (154 mmol) of 1.6 M n-butyllithium in hexane. The cooling bath was removed, 125 ml of HMPA added, and the mixture warmed to 0 °C. A solution of 14.6 g (70 mmol) of 7bromoheptanoic acid in 25 ml of HMPA was added and the mixture stirred at 0°C for 3 hr and then at 25°C for 24 hr. The crude acid was isolated in the usual manner and recrystallized from petroleum ether (b.p. 30-60°C) to give 4.2 g (39%) of 8decynoic acid as colorless plates, m.p. 41.5-42.5°C.

G. 9-Tetradecynoic acid, 16 To a solution of sodium ethoxide in ethanol (from 230 rag, 10 mmol of Na and 30 ml of ethanol) was added 1.52 ml (1.60 g, 10 mmol) of diethylmalonate. After heating at 70 °C for 2 hr, 2.2 g (11 mmol) of 1-chloro-7-dodecyne was added and the mixture refluxed for 18 hr. After cooling, the mixture was filtered, and the filtrate concentrated. The residue was dissolved in water, acidified, and extracted with ether. The ether extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was dissolved in 10 ml of ethanol and 120 ml of 3 N NaOH and refluxed for 22 hr. Isolation of the acidic product gave 700 mg (30%) of 9.tetra. decynoic acid as a colorless solid, m.p. 30-32 °C.

Acknowledgement We wish to thank the following members of our Physical Chemistry Department under the direction of Dr. R.P.W. Scott, for spectral data and elemental analyses: Dr. F. Scheidl, Dr. T. Williams, and Mr. S. Traiman. We gratefully acknowledge the expert technical assistance of Mr. G. Walsh.

References [1] Prostaglandins, Ann, N.Y. Acad. Sci. 180 (1971) [2] D.G. Ahem and D.T. Downing, Biochira. Biophys. Acta 210 (1970) 456 [3] D.T. Downing, A. Barve, F.D. Gunstone, F.R. Jacobsberg and M. Lieken Jie, Biochem. Biophys. Acta 280 (1972) 343 [4] K. Hofmann, W.M. O'Leary, C.W. Yoho and J.Y. Liu, J. Biol. Chem. 234 (1959) 1672

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